Long term trends in prevalence of neural tube defects in Europe: population based study.

STUDY QUESTION: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? METHODS: This was a population based, observational study using data on 11 353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. SUMMARY ANSWER AND LIMITATIONS: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10 000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. WHAT THIS STUDY ADDS: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. FUNDING, COMPETING INTERESTS, DATA SHARING: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

Potential blindness in children of patients with hereditary bone disease.

Mono- and bi-allelic mutations in the low-density lipoprotein receptor related protein 5 (LRP5) may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or persistent hyperplastic primary vitreous (PHPV). We report on a child affected with PHPV and carrying compound mutations. The father carried the splice mutation and suffered from severe bone fragility since childhood. The mother carried the missense mutation without any clinical manifestations. The genetic diagnosis of their child allowed for appropriate treatment in the father and for the detection of osteopenia in the mother. Mono- and bi-allelic mutations in LRP5 may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or PHPV. PHPV is a component of persistent fetal vasculature of the eye, characterized by highly variable expressivity and resulting in a wide spectrum of anterior and/or posterior congenital developmental defects, which may lead to blindness. We evaluated a family diagnosed with PHPV in their only child. The child presented photophobia during the first 3 weeks of life, followed by leukocoria at 2 months of age. Molecular resequencing of NDP, FZD4, and LRP5 was performed in the child and segregation of the observed mutations in the parents. At presentation, fundus examination of the child showed a retrolental mass in the right eye. Ultrasonography revealed retinal detachment in both eyes. Thorough familial analysis revealed that the father suffered from many fractures since childhood without specific fragility bone diagnosis, treatment, or management. The mother was asymptomatic. Molecular analysis in the proband identified two mutations: a c.[2091+2T>C] splice mutation and c.[1682C>T] missense mutation. We report the case of a child affected with PHPV and carrying compound heterozygous LRP5 mutations. This genetic diagnosis allowed the clinical diagnosis of the bone problem to be made in the father, resulting in better management of the family. It also enabled preventive treatment to be prescribed for the mother and accurate genetic counseling to be provided.

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

BACKGROUND: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. RESULTS: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. CONCLUSIONS: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.

The role of ultrasonography in the measurement of subcutaneous and visceral fat and its correlation with hepatic steatosis

Objective To evaluate the sonographic measurement of subcutaneous and visceral fat in correlation with the grade of hepatic steatosis. Materials and Methods In the period from October 2012 to January 2013, 365 patients were evaluated. The subcutaneous and visceral fat thicknesses were measured with a convex, 3–4 MHz transducer transversely placed 1 cm above the umbilical scar. The distance between the internal aspect of the abdominal rectus muscle and the posterior aortic wall in the abdominal midline was considered for measurement of the visceral fat. Increased liver echogenicity, blurring of vascular margins and increased acoustic attenuation were the parameters considered in the quantification of hepatic steatosis. Results Steatosis was found in 38% of the study sample. In the detection of moderate to severe steatosis, the area under the ROC curve was 0.96 for women and 0.99 for men, indicating cut-off values for visceral fat thickness of 9 cm and 10 cm, respectively. Conclusion The present study evidenced the correlation between steatosis and visceral fat thickness and suggested values for visceral fat thickness to allow the differentiation of normality from risk for steatohepatitis.

Transabdominal-pelvic-perineal (TAPP) anterolateral thigh flap: A new reconstructive technique for complex defects following extended abdominoperineal resection.

BACKGROUND: Abdominoperineal resection (APR) following radiotherapy is associated with a high rate of perineal wound complications. The anterolateral thigh (ALT) flap, combined with the vastus lateralis (VL) muscle, can cover complex perineal and pelvic anteroposterior defects. This is used for the first time transabdominally through the pelvis and the perineum (TAPP) in the infero-posterior directions; this technique has been described and illustrated in this study. METHODS: Among over 90 patients who underwent perineal reconstruction between May 2004 and June 2011, six patients presented high-grade tumours invading perineum, pelvis and sacrum, thereby resulting in a continuous anteroposterior defect. ALT + VL TAPP reconstructions were performed after extended APR and, subsequently, sacrectomy. Patients were examined retrospectively to determine demographics, operative time, complications (general and flap-related), time to complete healing and length of hospital stay. Long-term flap coverage, flap volume stability and functional and aesthetic outcomes were assessed. RESULTS: Mean operating time of the reconstruction was 290 min. No deaths occurred. One patient presented partial flap necrosis. Another patient presented a novel wound dehiscence after flap healing, due to secondary skin dissemination of the primary tumour. Following volumetric flap analysis on serial post-operative CT scans, no significant flap atrophy was observed. All flaps fully covered the defects. No late complications such as fistulas or perineal hernias occurred. Donor-site recovery was uneventful with no functional deficits. CONCLUSIONS: The use of the ALT + VL flap transabdominally is an innovative method to reconstruct exceptionally complex perineal and pelvic defects extending up to the lower back. This flap guarantees superior bulk, obliterating all pelvic dead space, with the fascia lata (FL) supporting the pelvic floor.

Thermoplastic bioactive composite – with special reference to dissolution behaviour and tissue response

Bioactive glasses are surface-active ceramic materials which support and accelerate bone growth in the body. During the healing of a bone fracture or a large bone defect, fixation is often needed. The aim of this thesis was to determine the dissolution behaviour and biocompatibility of a composite consisting of poly(ε-caprolactone-co-DL-lactide) and bioactive glass (S53P4). In addition the applicability as an injectable material straight to a bone defect was assessed. In in vitro tests the dissolution behaviour of plain copolymer and composites containing bioactive glass granules was evaluated, as well as surface reactivity and the material’s capability to form apatite in simulated body fluid (SBF). The human fibroblast proliferation was tested on materials in cell culture. In in vivo experiments, toxicological tests, material degradation and tissue reactions were tested both in subcutaneous space and in experimental bone defects. The composites containing bioactive glass formed a unified layer of apatite on their surface in SBF. The size and amount of glass granules affected the degradation of polymer matrix, as well the material’s surface reactivity. In cell culture on the test materials the human gingival fibroblasts proliferated and matured faster compared with control materials. In in vitro tests a connective tissue capsule was formed around the specimens, and became thinner in the course of time. Foreign body cell reactions in toxicological tests were mild. In experimental bone defects the specimens with a high concentration of small bioactive glass granules (<45 μm) formed a dense apatite surface layer that restricted the bone ingrowth to material. The range of large glass granules (90-315 μm) with high concentrations formed the best bonding with bone, but slow degradation on the copolymer restricted the bone growth only in the superficial layers. In these studies, the handling properties of the material proved to be good and tissue reactions were mild. The reactivity of bioactive glass was retained inside the copolymer matrix, thus enabling bone conductivity with composites. However, the copolymer was noticed to degradate too slowly compared with the bone healing. Therefore, the porosity of the material should be increased in order to improve tissue healing.

Defects in Persistent Luminescence Materials

Persistent luminescence materials can store energy from solar radiation or artificial lighting and release it over a period of several hours without a continuous excitation source. These materials are widely used to improve human safety in emergency and traffic signalization. They can also be utilized in novel applications including solar cells, medical diagnostics, radiation detectors and structural damage sensors. The development of these materials is currently based on methods based on trial and error. The tailoring of new materials is also hindered by the lack of knowledge on the role of their intrinsic and extrinsic lattice defects in the appropriate mechanisms. The goal of this work was to clarify the persistent luminescence mechanisms by combining ab initio density functional theory (DFT) calculations with selected experimental methods. The DFT approach enables a full control of both the nature of the defects and their locations in the host lattice. The materials studied in the present work, the distrontium magnesium disilicate (Sr₂MgSi₂O₇) and strontium aluminate (SrAl₂O₄) are among the most efficient persistent luminescence hosts when doped with divalent europium Eu²⁺ and co-doped with trivalent rare earth ions R³⁺ (R: Y, La-Nd, Sm, Gd-Lu). The polycrystalline materials were prepared with the solid state method and their structural and phase purity was confirmed by X-ray powder diffraction. Their local crystal structure was studied by high-resolution transmission electron microscopy. The crystal and electronic structure of the nondoped as well as Eu²⁺, R^2+/3+ and other defect containing materials were studied using DFT calculations. The experimental trap depths were obtained using thermoluminescence (TL) spectroscopy. The emission and excitation of Sr₂MgSi₂O₇:Eu²+,Dy³⁺ were also studied. Significant modifications in the local crystal structure due to the Eu²⁺ ion and lattice defects were found by the experimental and DFT methods. The charge compensation effects induced by the R³⁺ co-doping further increased the number of defects and distortions in the host lattice. As for the electronic structure of Sr₂MgSi₂O₇ and SrAl₂O₄, the experimental band gap energy of the host materials was well reproduced by the calculations. The DFT calculated Eu²⁺ and R^2+/3+ 4fn as well as 4f^n-15d¹ ground states in the Sr₂MgSi₂O₇ band structure provide an independent verification for an empirical model which is constructed using rather sparse experimental data for the R³⁺ and especially the R²⁺ ions. The intrinsic and defect induced electron traps were found to act together as energy storage sites contributing to the materials’ efficient persistent luminescence. The calculated trap energy range agreed with the trap structure of Sr₂MgSi₂O₇ obtained using TL measurements. More experimental studies should be carried out for SrAl₂O₄ to compare with the DFT calculations. The calculated and experimental results show that the electron traps created by both the rare earth ions and vacancies are modified due to the defect aggregation and charge compensation effects. The relationships between this modification and the energy storage properties of the solid state materials are discussed.

Facial paralysis and vestibular syndrome in feedlot cattle in Argentina

This paper reports 6 outbreaks of neurological disease associated with paralysis of the facial and vestibulocochlear nerves caused by intracranial space occupying lesions in feedlot cattle. The clinical signs observed were characterized by head tilt, uni or bilateral drooping and paralysis of the ears, eyelid ptosis, keratoconjunctivitis, and different degrees of ataxia. Morbidity and mortality rates ranged from 1.1 to 50% and 0 to 1%, respectively. Gross lesions observed included yellow, thickened leptomeninges, and marked enlargement of the roots of cranial nerves VII (facial) and VIII (vestibulocochlear). Histopathologically, there was severe, chronic, granulomatous meningitis and, in one case, chronic, granulomatous neuritis of the VII and VIII cranial nerves. Attempts to identify bacterial, viral, or parasitic agents were unsuccessful. Based on the morphologic lesions, the clinical condition was diagnosed as facial paralysis and vestibular syndrome associated with space occupying lesions in the meninges and the cranial nerves VII and VIII. Feedlot is a practice of growing diffusion in our country and this is a first report of outbreaks of facial paralysis and vestibular disease associated with space occupying lesions in Argentina.

A study of the facial aging - a multidisciplinary approach

This paper describes a mathematical and graphical model for face aging. It considers the possibility of predicting the aging process by offering an initial quantification of this process as it applies to the face. It is concerned with physical measurements and a general law of time dependence. After measuring and normalizing a photograph of a person, one could predict, with a known amount of error, the appearance of that person at a different age. The technique described has served its purpose successfully, with a representative amount of patient data behaving sufficiently near the general aging curve of each parameter. That model uses a warping technique to emulate the aging changes on the face of women. Frequently the warping methods are based on the interpolation between images or general mathematical functions to calculate the pixel attributes. The implemented process considers the age features of selected parts of a face such as the face outline and the shape of the lips. These age features were obtained by measuring the facial regions of women that have been photographed throughout their lives. The present work is first concerned with discussing a methodology to define the aging parameters that can be measured, and second with representing the age effects graphically.

Epidemiology, management and outcome of facial injuries

Dental injuries are common and the incidence of maxillofacial injuries has increased over the recent decades in Finland. Accidental injuries are the global leading cause of death among children over the age of one year and among adults under the age of 40 globally. Significant resources and costs are needed for the treatment of these patients. The prevention is the most economical way to reduce trauma rates and costs. For the prevention it is crucial to know the prevalences, incidences and risk factors related to injuries. To improve the quality of treatment, it is essential to explore the causes, trauma mechanisms and management of trauma. The above mentioned was the aim of this thesis. With a large epidemiological cohort study (5737 participants) it was possible to estimate lifetime prevalence of and risk factors for dental trauma in general population (Study I). The prevalence of dental fractures was 43% and the prevalence of dental luxations and avulsions was 14%. Male gender, a history of previous non-dental injuries, mental distress, overweight and high alcohol consumption were positively associated with the occurrence of dental injuries Study II was conducted to explore the differences in type and multiplicity of mandibular fractures in three different countries (Canada, Finland and Kuwait). This retrospective study showed that the differences in mandibular fracture multiplicity and location are based on different etiologies and demographic patterns. This data can be exploited for planning of measures to prevent traumatic facial fractures. The etiology, management and outcome of 63 pediatric skull base fracture (Study III) and 20 pediatric frontobasal fracture patients (Study IV) were explored. These retrospective studies showed that, both skull base fracture and frontobasa fracture are rare injuries in childhood and although intracranial injuries and morbidity are frequent, permanent neurological or neuropsychological deficits are infrequent. A systematic algorithm (Study V) for computer tomography (CT) image review was aimed at clinicians and radiologists to improve the assessment of patients with complex upper midface and cranial base trauma. The cohort study was cross sectional and data was collected in the Turku and Oulu University Hospitals. A novel image-reviewing algorithm was created to enhance the specificity of CT for the diagnosis of frontobasal fractures. The study showed that an image-viewing algorithm standardizes the frontobasal trauma detection procedure and leads to better control and assessment. The purpose of the retrospective subcranial craniotomy study (VI) was to review the types of frontobasal fractures and their management, complications and outcome when the fracture is approached subcranially. The subcranial approach appears to be successful and have a reasonably low complication rate. It may be recommended as the technique of choice in multiple and the most complicated frontal base fractures where the endoscopic endonasal approach is not feasible.

Rare adverse events associated with oral poliovirus vaccine in Brazil

Oral poliovirus vaccine (OPV) developed by A. Sabin has been effectively used to control poliomyelitis in Brazil, and the last case with the isolation of a wild poliovirus strain occurred in March 1989. Although the vaccine controlled the circulation of wild strains and poliomyelitis cases associated with these strains were not detected during the last eight years, rare cases classified as vaccine-associated paralytic poliomyelitis (VAPP) have been detected. Molecular characterization studies of poliovirus strains isolated from VAPP cases and from healthy contacts have confirmed that the isolates are derived from the Sabin vaccine strains and also detected genomic modifications known or suspected to increase neurovirulence such as mutations and recombination. The molecular characterization of polioviruses isolated during the last eight years from paralysis cases classified as Guillain-Barré (GBS) syndrome and transverse myelitits (TM), and from facial paralysis (FP) cases also confirmed the vaccine origin of the strains and demonstrated mutations known to increase neurovirulence. Analysis of the epidemiologic data of these GBS, TM and FP cases demonstrated that in most of them the last OPV dose was given months or years before the onset of the disease and the isolation of the polioviruses. The temporal association between the isolation of these strains and the GBS, TM and FP suggested that the Sabin vaccine-derived poliovirus strains could also rarely trigger the diseases.

Association of Alport's syndrome with HLA-DR2 antigen in a group of unrelated patients

A few family studies have evaluated HLA antigens in Alport's syndrome; however, there are no large population studies. In the present report, we studied 40 unrelated white patients with Alport's syndrome seen at the Unit of Renal Transplantation, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil. HLA-A, -B, -DR and -DQ antigens were typed using a complement-dependent microlymphocytotoxicity assay. A control white population (N = 403) from the same geographical area was also typed for HLA antigens. Although the frequencies of HLA-A and -B antigens of patients were not statistically different from controls, the frequency of HLA-DR2 antigen observed in patients (65%) was significantly increased in relation to controls (26%; P<0.001). The relative risk and etiologic fraction for HLA-DR2 antigen were 5.2 and 0.525, respectively. Although few immunological abnormalities have been shown in Alport's syndrome, in this report we emphasize the association of HLA molecules and Alport's syndrome. Besides the well-known inherited molecular defects encoded by type IV collagen genes in Alport's syndrome, the major histocompatibility alleles may be in linkage disequilibrium with these defective collagen genes

Pupil size following dark adaptation in patients with retinitis pigmentosa

According to the equivalent light hypothesis, molecular defects in the photoreceptor lead to a continuous activation of the photoreceptor cascade in a manner equivalent to real light. The consequences in diseases such as retinitis pigmentosa (RP) are as disruptive to the cells as real light. Two forms of the equivalent light hypothesis can be distinguished: strong - mutations in rhodopsin or other cascade proteins in some forms of RP continuously excite the visual phototransduction cascade; weak - disruption of outer segments in all patients with RP eliminates circulating dark current and blocks neurotransmitter release in a manner similar to real light. Both forms of the equivalent light hypothesis predict that pupils of patients with RP will be constricted like those of normal subjects in the light. The purpose of this study was to test the equivalent light hypothesis by determining whether steady-state pupil diameter following full dark adaptation is abnormally small in any of a sample of patients with RP. Thirty-five patients with RP and 15 normal subjects were tested. Direct steady-state pupillometric measures were obtained from one eye in a full-field dome after 45 min of dark adaptation by videotaping the pupil with an infrared camera. Mean pupil diameter in the dark was comparable (t = -0.15, P = 0.88) between patients with RP (6.85 ± 0.58 mm) and normal subjects (6.82 ± 0.76 mm). The results of the present study are clearly counter to the prediction of the second (weaker) form of the equivalent light hypothesis.

ß-Spectrin São PauloII, a novel frameshift mutation of the ß-spectrin gene associated with hereditary spherocytosis and instability of the mutant mRNA

Hereditary spherocytosis (HS) is a common inherited anemia characterized by the presence of spherocytic red cells. Defects in several membrane protein genes have been involved in the pathogenesis of HS. ß-Spectrin-related HS seems to be common. We report here a new mutation in the ß-spectrin gene coding region in a patient with hereditary spherocytosis. The patient presented acanthocytosis and spectrin deficiency and, at the DNA level, a novel frameshift mutation leading to HS, i.e., a C deletion at codon 1392 (ß-spectrin São PauloII), exon 20. The mRNA encoding ß-spectrin São PauloII was very unstable and the mutant protein was not detected in the membrane or in other cellular compartments. It is interesting to note that frameshift mutations of the ß-spectrin gene at the 3' end allow the insertion of the mutant protein in the red cell membrane, leading to a defect in the auto-association of the spectrin dimers and consequent elliptocytosis. On the other hand, ß-spectrin São PauloII protein was absent in the red cell membrane, leading to spectrin deficiency, HS and the presence of acanthocytes.

Protein defects in neuromuscular diseases

Muscular dystrophies are a heterogeneous group of genetically determined progressive disorders of the muscle with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is highly variable, ranging from severe congenital forms with rapid progression to milder forms with later onset and a slower course. In recent years, several proteins from the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), from the extracellular matrix (alpha2-laminin, collagen VI), from the sarcomere (telethonin, myotilin, titin, nebulin), from the muscle cytosol (calpain 3, TRIM32), from the nucleus (emerin, lamin A/C, survival motor neuron protein), and from the glycosylation pathway (fukutin, fukutin-related protein) have been identified. Mutations in their respective genes are responsible for different forms of neuromuscular diseases. Protein analysis using Western blotting or immunohistochemistry with specific antibodies is of the utmost importance for the differential diagnosis and elucidation of the physiopathology of each genetic disorder involved. Recent molecular studies have shown clinical inter- and intra-familial variability in several genetic disorders highlighting the importance of other factors in determining phenotypic expression and the role of possible modifying genes and protein interactions. Developmental studies can help elucidate the mechanism of normal muscle formation and thus muscle regeneration. In the last fifteen years, our research has focused on muscle protein expression, localization and possible interactions in patients affected by different forms of muscular dystrophies. The main objective of this review is to summarize the most recent findings in the field and our own contribution.